A5087508311- Glioma Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Biochemical and Molecular Research
- Cancer Mechanisms and Therapy
- Blood properties and coagulation
- Cancer-related gene regulation
- Single-cell and spatial transcriptomics
- Platelet Disorders and Treatments
- Protein Degradation and Inhibitors
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Cancer Research and Treatments
- Bioinformatics and Genomic Networks
- Heparin-Induced Thrombocytopenia and Thrombosis
- Cell Image Analysis Techniques
- Pancreatic function and diabetes
- Estrogen and related hormone effects
- Cancer Genomics and Diagnostics
- Ubiquitin and proteasome pathways
- Gene Regulatory Network Analysis
- Microbial metabolism and enzyme function
- Radiopharmaceutical Chemistry and Applications
- Endoplasmic Reticulum Stress and Disease
- Cancer Cells and Metastasis
Discovery Institute
2015-2024
University of Pittsburgh
2015-2024
Icahn School of Medicine at Mount Sinai
2022
Broad Institute
2009-2018
Computational Diagnostics (United States)
2016
Massachusetts Institute of Technology
2009-2012
Harvard University
1989-2012
McGill University
2011
New York University
2009
Brooklyn Hospital Center
2009
Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively cancer cells in vitro and vivo. This compound was found elevate cellular levels of reactive oxygen species (ROS) cell lines. The synthesis 80 piperlongumine analogs has revealed structural modifications that retain, enhance, ablate key piperlongumine-associated effects on cells, including elevation ROS, death, selectivity for over nontransformed types. Structure/activity relationships suggest...
Given the clinical relevance of ESR1 mutations as potential drivers resistance to endocrine therapy, this study used sensitive detection methods determine frequency in primary and metastatic breast cancer, cell-free DNA (cfDNA).Six (K303R, S463P, Y537C, Y537N, Y537S, D538G) were assessed by digital droplet PCR (ddPCR), with lower limits 0.05% 0.16%, tumors (n = 43), bone 12) brain metastases 38), cfDNA 29). Correlations between lesions single (1 patient) or serial blood draws (4 patients)...
Presenilins are integral membrane protein involved in the production of amyloid β-protein. Mutations presenilin-1 and -2 gene associated with familial Alzheimer's disease thought to alter γ-secretase cleavage β-amyloid precursor protein, leading increased longer more amyloidogenic forms Aβ, 4-kDa β-peptide. Here, we show that radiolabeled inhibitors bind mammalian cell membranes, a benzophenone analog specifically photocross-links three major polypeptides. A positive correlation is observed...
Mutations in the estrogen receptor alpha (ERα) 1 gene (ESR1) are frequently detected ER+ metastatic breast cancer, and there is increasing evidence that these mutations confer endocrine resistance cancer patients with advanced disease. However, their functional role not well-understood, at least part due to a lack of ESR1 mutant models. Here, we describe generation characterization genome-edited T47D MCF7 cell lines two most common mutations, Y537S D538G. Genome editing was performed using...
The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels a transcript encoding the serine/threonine kinase STK33 was selectively toxic KRAS-dependent cancer cell lines, suggesting small-molecule inhibitors might target cancers. To test this hypothesis, we initiated high-throughput screen using compounds Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one these, quinoxalinone derivative,...
To characterize genes that become upregulated with malignant transformation of human hepatocytes, a library monoclonal antibodies was produced against the FOCUS hepatocellular carcinoma cell line. Antibody FB-50 reacted an antigen highly expressed in 4 10 primary carcinomas, all 20 cholangiocarcinomas we studied, and variety transformed lines. This also neoplastic epithelial cells breast colon carcinomas contrast to its low level expression normal hepatocytes non-neoplastic cells. Among...
Candida albicans, the most common human pathogenic fungus, can establish a persistent lethal infection in intestine of microscopic nematode Caenorhabditis elegans. The C. elegans–C. albicans model was previously adapted to screen for antifungal compounds. Modifications this have been made facilitate high-throughput assay including co-inoculation nematodes with and instrumentation allowing precise dispensing worms into wells, eliminating two labor-intensive steps. This method utilized library...
Approximately 30% of human cancers harbor oncogenic gain-of-function mutations in KRAS. Despite interest KRAS as a therapeutic target, direct blockade function with small molecules has yet to be demonstrated. Based on experiments that lower mRNA levels protein kinases, KRAS-dependent cancer cells were proposed have unique requirement for the serine/threonine kinase STK33. Thus, it was suggested small-molecule inhibitors STK33 might benefit these cancers. Here, we describe development...
Rabbit hepatocyte surface-expressed tissue (type II) transglutaminase is shown to act as a binding site for fibrinogen or fibronectin and covalently incorporate these glycoproteins, in addition itself, into extracellular high molecular weight complexes. This concept supported by the observation that nonpeptidyl, active site-directed inactivator (L683685) elicited concentration-dependent (0.1-10 microM) decreases calcium-dependent covalent cross-linking of 125I-fibrinogen, 125I-fibronectin,...
The physiologic role of several transglutaminases could be more precisely defined with the development specific inhibitors for these enzymes. In addition, plasma transglutaminase (fXIIIa) may have therapeutic utility in treatment thrombosis. For purposes, inactivation fXIIIa and human erythrocyte (HET) by 2-[(2-oxopropyl)thio]imidazolium derivatives, which comprise a novel class inactivators, was studied. As example, 1,3,4,5-tetramethyl-2-[(2-oxopropyl)thio]imidazolium chloride (III)...
Matrix metalloproteinase (MMP)-activated prodrugs were formed by coupling MMP-cleavable peptides to doxorubicin. The resulting conjugates excellent in vitro substrates for MMP-2, -9, and -14. HT1080, a fibrosarcoma cell line, was used as model system test these because cells, like tumor stromal fibroblasts, expressed several MMPs. In cultured HT1080 simple primarily metabolized neprilysin, membrane-bound metalloproteinase. MMP-selective metabolism cells obtained designing that good MMP but...
Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers ROS may selectively kill various vitro vivo models. We used a high-throughput screening approach identify several hundred human osteosarcoma cell line. A minority these compounds diminished the viability lines, indicating elevation by small molecules is insufficient induce death lines. Three chemical probes...
One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic a population cells, it not routinely evaluated or reported. The standard practice cell-based, high content assays been assume normal distribution report well-to-well average value with deviation. To address this important...
Aspartyl (asparaginyl) beta-hydroxylase which specifically hydroxylates 1 Asp or Asn residue in certain epidermal growth factor-like domains of a number proteins, has been previously purified to apparent homogeneity from detergent-solubilized bovine liver microsomes (Wang, Q., VanDusen, W. J., Petroski, C. Garsky, V. M., Stern, A. and Friedman, P. (1991) J. Biol. Chem. 266, 14004-14010). Three oligonucleotides, corresponding three amino acid sequences the hydroxylase, were used screen cDNA...
Vitamin K-dependent bovine protein S has been shown to contain a posttranslationally hydroxylated asparagine within conserved sequence in three of its epidermal growth factor (EGF)-like domains. In review amino acid sequences deduced from cDNA data, we have observed that containing potential hydroxylation site exists EGF-like domains variety functionally diverse proteins. We studied number these and report the presence erythro-beta-hydroxyasparagine (e-beta Hyn) non-vitamin proteins: plasma...
beta-Hydroxylation of aspartic acid is a post-translational modification that occurs in several vitamin K-dependent coagulation proteins. By use synthetic substrate comprised the first epidermal growth factor-like domain human factor IX and either mouse L-cell extracts or rat liver microsomes as source enzyme, vitro aspartyl beta-hydroxylation was accomplished. Aspartyl beta-hydroxylase appears to require same cofactors known alpha-ketoglutarate-dependent dioxygenases. The hydroxylation...
Clearance of intact parathyroid hormone (PTH) from blood is associated with rapid uptake by liver and kidney, limited proteolysis tissue endopeptidases and, within minutes, appearance circulating carboxyl-(COOH)-terminal PTH fragments. The fate the corresponding amino(NH2)-terminal portion during this peripheral metabolism still unknown, however. To determine this, we have employed [35S]bovine (bPTH) labeled to high specific activity at NH2-terminal methionines, which permits direct...